In neuroscience, plasticity has traditionally been studied at the synaptic level in the context of learning and memory. Results from our studies of monkeys suggest that the learning-like process of coping with stress has broader effects on plasticity in prefrontal development. Exposure to intermittent social separations that simulate a naturally occurring but stressful transition in development increases ventromedial and not dorsolateral prefrontal cortical volumes. Increased ventromedial prefrontal cortical volumes reflect surface area expansion and coincide with increased white matter myelination inferred from neuroimaging. In published studies of the same monkeys, we previously reported that intermittent separations diminish subsequent stress-levels of cortisol, increase exploration of novel situations, and enhance prefrontal-dependent cognitive control of behavior [15
]. Taken together, these findings suggest a role for prefrontal neuroadaptations in arousal regulation and resilience.
The cellular basis of stress-induced prefrontal neuroadaptations is unknown. Prefrontal cortical cell proliferation, dendritic elaboration, and synapse formation are largely complete soon after parturition in human and nonhuman primates [38
]. Around puberty, prefrontal cortical volumes then undergo a significant decline that corresponds with synaptic pruning [40
] and possibly neuronal cell loss [41
]. Diminished usage-dependent cell loss and selective retention of synaptic connections in ventromedial prefrontal cortex may accompany the learning-like process of coping with early life stress. This possibility is consistent with evidence of experience-dependent prefrontal plasticity in adolescent rats [42
Unlike the pattern of prefrontal gray matter growth and regression, prefrontal white matter increases linearly throughout childhood and adolescence in primates [30
]. White matter is composed of axons sheathed in myelin produced by oligodendrocytes, and increased myelination induced by early experiences appears to affect information processing in distributed neural networks [29
]. Despite evidence that coping with stress depends on myelinated prefrontal cortical and subcortical interconnections [24
], myelination is seldom considered in discussions of neural plasticity as a mechanism for experience-dependent resilience [45
The observation that stress affects ventromedial and not dorsolateral prefrontal white matter interconnections corresponds with structural and functional differences between these regions. The dorsolateral region is primarily comprised of granular cortex [48
] and its connections are consistent with executive functions, i.e. attention, planning, and working memory [50
]. The ventromedial region largely consists of agranular cortex [48
] and its connections indicate a role in visceral and sensory information integration, autonomic and neuroendocrine systems regulation, and the control of adaptive emotional behavior [44
Effect sizes for stress-induced prefrontal neuroadaptations are small but similar in magnitude to brain changes induced by environmental enrichment in marmoset monkeys [54
] and rats [55
]. Enrichment entails exposure to novel inanimate and/or social stimulation [57
] and elicits neuroendocrine indications of mild stress in rats [58
]. After exposure to enrichment, however, rats show diminished anxiety [57
] and enhanced prefrontal-dependent learning [59
] compared to nonenriched controls. These findings combined with our studies suggest that enrichment effects may be mediated, in part, by the process of coping with stress.
Controlled exposure to stress-related cues is also a feature of resiliency training for people that work in conditions where performance in the face of adversity is required, e.g. medical and military personnel, aviators, police, firefighters, and rescue workers [7
]. A similar process likewise occurs during cognitive behavior exposure therapy for stress-induced psychopathology. Patients are taught to confront their stress-related memories in imagination and then to interact with stress-inducing objects or situations in vivo. Repeated exposure to stress-related cues is thought to activate cognitive and emotional processing within and between exposure sessions, and thereby modify erroneous conditions that underlie the disorder [61
]. Although exposure therapy for patients and resiliency training for healthy humans are administered by professional psychologists and psychiatrists, our findings support Epstein's [63
] suggestion that these interventions build on a basic stress coping process that tends to occur spontaneously without formal instruction or guidance.
All studies have their limitations and ours is no exception. The ratio of males to females is skewed toward females and our findings may or may not hold true for males. The surface features of cortex we used to differentiate prefrontal boundaries on T1-weighted images only roughly coincide with conventional maps based on cytoarchitectural borders. Increased fractional anisotropy determined by diffusion tensor imaging may reflect microstructural changes other than increased myelination, e.g. increased cell packing densities or larger nerve fiber diameters. The limitations of noninvasive neuroimaging are offset by opportunities for longitudinal follow-up studies of these adolescent monkeys. Such studies are needed to determine whether stress inoculation-induced prefrontal structural and functional adaptations persist into adulthood.